Since the discovery of penicillin, pharmaceutical companies have produced more than one hundred antibacterial agents to combat a wide variety of bacterial infections. In the past several years, there has been rapid emergence of bacterial resistance to several of these antibiotics. The multidrug resistance among these bacterial pathogens may also be due to mutation leading to more virulent clinical isolation, the most disturbing milestone has been the acquisition of resistance to vancomycin, an antibiotic generally regarded as the agent of last resort for serious Gram-positive infections. This growing multidrug resistance has recently rekindled interest in the search for new structural class of antibiotic that inhibit or kill these bacteria possibly by novel mechanisms.
A problem of larger dimension is the increasing incidence of the more virulent, methicillin-resistant Staphylococcus aureas (MRSA) among clinical isolates found worldwide. As with vancomycin resistant organisms, many MRSA strains are resistant to most of the known antibiotics, but MRSA strains have remained sensitive to vancomycin. However, in view of the increasing reports of vancomycin resistant clinical isolates and growing problem of bacterial resistance, there is an urgent need for new molecular entities effective against the emerging and currently problematic Gram-positive organisms.
Recently, several oxazolidinones have been discovered, which inhibit protein synthesis by binding to the 50S-ribosomal subunit which is close to the site to which chloramphenicol and lincomycin bind but their mode of action is mechanistically distinct from these two antibiotics.
Various 1,2,3-triazoles, 1,2,4-triazoles and benzotriazoles have been reported to show various biological activities and have therefore found applications in medicinal chemistry. The literature survey shows the use of 1,2,3-triazoles, for the treatment of neuropathic pain and associated hyperalgesia, including trigeminal and herpectic neuralgia, diabetic neuropathic pain, migraine, causalgia and deafferentation syndromes such as brachial plexus avulsion, an anticoccidiostat, as antiproliferative agents, for antimetastatic activity in a model of ovarian cancer progression, for anti-inflammatory effect, controlling activity against noxious organisms, for the treatment of ischemia, anti-human immunodeficiency virus activity etc.
However, there are no reports of 1,2,3-triazole derivatives of the present invention being used for treating bacterial infections, specifically against multidrug resistant strains.
The new class of triazoles of the present invention is useful for the treatment of a number of resistant and sensitive gram-positive strains both in vitro and in vivo.
(a) Chem. Pharm. Bull. 48(12), 1935–1946 (2000) discloses the triazoles of formula (ia) and (ib), which are reported as antifungal agents,
where X represents N, CH or CH2.
U.S. Pat. No. 6,054,471 discloses fluorinated triazoles of the formula (ii), which are reported for the treatment of neuropathic pain and associated hyperalgesia, including trigeminal and herpectic neuralgia, diabetic neuropathic pain, migraine, causalgia and deafferentation syndromes such as brachial plexus avulsion,
where Ph is an o-fluorinated phenyl group which may be additionally substituted by 1 or 2 halogen atoms selected from fluorine and chlorine; R11 is hydrogen, carbamoyl, N-(C2–C5)alkanoylcarbamoyl or N,N-di-(C1–C4)alkylcarbamoyl; R21 is carbamoyl, N-(C2–C5)alkanoylcarbamoyl or N,N-di-(C1–C4)alylcarbamoyl.
An example of this class of compounds is shown in formula (iia),

(c) J. Med. Chem., 2843, 1991 discloses compound of formula (iii), which is an anticoccidiostat and also been found to have antiproliferative activity in several disease models and to posses antimetastatic activity in a model of ovarian cancer progression,

(d) J. Heterocycl. Chem., 609, 1989 discloses compound of formula (iv), which is reported for anti-inflammatory effects,

(e) EPO publication no 0304221 A2 discloses compounds of formula (v), which are reported as antiproliferative reagents,
where R′1 represents

wherein p is 0 to 2; m is 0 to 4; and n is 0 to 5; X is O, S, SO, SO2, CO, CHCN, CH2 or C═NR6 where R6 is hydrogen, loweralkyl, hydroxy, loweralkoxy, amino loweralkylamino. diloweralkylamino or cyano, and, R′4 and R′5 are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, carbalkoxy, trifluoromethoxy, acetamido, loweralkylthio, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio. trifluoromethylsuifinyl, or trifluoromethylsulfonyl;
R′2 is amino, mono or diloweralkylamino, acetamido, acetimido, ureido, formamido, or guanidino; and
R′3 is carbamoyl, cyano. carbazoyl, amidino or N-hydroxycarbamoyl.
An example of this class of compounds is shown in formula (va),
